PROJECT SUMMARY The short term objectives of this KO2 proposal are: 1) to increase the time devoted to conduct and complete experiments of a recently awarded RO1; and 2) to complete exercises designed to enhance and enrich the applicants focus and expertise in the areas of aging and epigenetics. The long-term objective of the KO2 is to effectively utilize both 1) and 2) to enhance the training of graduate students, post docs, faculty (not currently practicing in the field of aging) and undergraduates, in particular, in aging research and to obtain additional support in future years. The research environment at the University of North Dakota School of Medicine & Health Sciences is active and growing. Two major NIH grants (INBRE, COBRE) over the last 8 years have increased the resources available to the basic scientists. The Proteomics/Mass Spectrometry core, a core in Bioinformatics that is under development and the Center for Biomedical Research (animal facilities) will be utilized by the applicant. The applicant has developed an active research program at UND with the current tools available and plans to increase those activities during the period of the award and beyond. The objective of the science integral to this proposal is to delineate mechanisms of the beneficial effects of growth hormone deficiency on mitochondrial function, stress resistance and health span. Our research has been focused on understanding the hypothesis that in long living animals, an upregulation of thiol metabolism leads to greater protection from cellular stress. The applicant's work has established that reduced growth hormone (GH) signaling is a major player in longevity assurance. The global hypothesis to be tested is that thiol metabolism plays a key role in aging and that GH modulates key components of this pathway ultimately leading to changes in health span (via stress resistance/protection) and lifespan. Thus, reduced GH signaling confers a biologic advantage to dwarf mice leading to better scavenging of toxic metabolic byproducts, altered mitochondrial function and enhanced longevity. To further address and define this global hypothesis the applicant plans to elucidate the relationship between GH, thiol metabolism and cellular protection by: 1) directly linking the enhanced respiratory and antioxidative activities in dwarf mice to increased mitochondrial GSH and glutathionylation of these proteins; 2) providing direct evidence that the lack of GH is responsible for substrate-specific enhancement of the GST system; 3) defining the changes in thiol metabolism linked to stress resistance and longevity following altered dietary MET; and 4) establishing the first epigenomic profile of a long-living mouse. Determining GH-dependent pathways and mechanisms may suggest therapeutic interventions to enhance stress resistance, delay aging, treat aging-related disorders and extend health span in humans.